Department of Biochemistry, University of Otago, Dunedin, New Zealand.
PLoS One. 2010 Oct 21;5(10):e13544. doi: 10.1371/journal.pone.0013544.
The Trp(620) allotype of PTPN22 confers susceptibility to rheumatoid arthritis (RA) and certain other classical autoimmune diseases. There has been a report of other variants within the PTPN22 locus that alter risk of RA; protective haplotype '5', haplotype group '6-10' and susceptibility haplotype '4', suggesting the possibility of other PTPN22 variants involved in the pathogenesis of RA independent of R620W (rs2476601). Our aim was to further investigate this possibility.
A total of 4,460 RA cases and 4,481 controls, all European, were analysed. Single nucleotide polymorphisms rs3789607, rs12144309, rs3811021 and rs12566340 were genotyped over New Zealand (NZ) and UK samples. Publically-available Wellcome Trust Case Control Consortium (WTCCC) genotype data were used.
The protective effect of haplotype 5 was confirmed (rs3789607; (OR = 0.91, P = 0.016), and a second protective effect (possibly of haplotype 6) was observed (rs12144309; OR = 0.90, P = 0.021). The previously reported susceptibility effect of haplotype 4 was not replicated; instead a protective effect was observed (rs3811021; OR = 0.85, P = 1.4×10(-5)). Haplotypes defined by rs3789607, rs12144309 and rs3811021 coalesced with the major allele of rs12566340 within the adjacent BFK (B-cell lymphoma 2 (BCL2) family kin) gene. We, therefore, tested rs12566340 for association with RA conditional on rs2476601; there was no evidence for an independent effect at rs12566340 (P = 0.76). Similarly, there was no evidence for an independent effect at rs12566340 in type 1 diabetes (P = 0.85).
We have no evidence for a common variant additional to rs2476601 within the PTPN22 locus that influences the risk of RA. Arg620Trp is almost certainly the single common causal variant.
PTPN22 基因的 Trp(620)同种型易患类风湿关节炎（RA）和某些其他经典自身免疫性疾病。已经有报道称 PTPN22 基因座内的其他变体改变了 RA 的风险；保护性单倍型“5”、单倍型组“6-10”和易感性单倍型“4”，表明其他 PTPN22 变体可能参与了 RA 的发病机制，而与 R620W（rs2476601）无关。我们的目的是进一步研究这种可能性。
共分析了 4460 例 RA 病例和 4481 例对照，均为欧洲人。在新西兰（NZ）和英国样本中对单核苷酸多态性 rs3789607、rs12144309、rs3811021 和 rs12566340 进行了基因分型。使用了公开的惠康信托基金病例对照联盟（WTCCC）基因型数据。
证实了单倍型 5 的保护作用（rs3789607；（OR = 0.91，P = 0.016），并且观察到了第二个保护作用（可能是单倍型 6）（rs12144309；OR = 0.90，P = 0.021）。先前报道的单倍型 4 的易感性效应未被复制；相反，观察到了保护作用（rs3811021；OR = 0.85，P = 1.4×10(-5)）。由 rs3789607、rs12144309 和 rs3811021 定义的单倍型与相邻 BFK（B 细胞淋巴瘤 2（BCL2）家族激酶）基因中 rs12566340 的主要等位基因合并。因此，我们在 rs2476601 条件下对 rs12566340 与 RA 进行了关联测试；rs12566340 没有独立作用的证据（P = 0.76）。同样，在 1 型糖尿病中，rs12566340 也没有独立作用的证据（P = 0.85）。
我们没有发现 PTPN22 基因座内除 rs2476601 之外影响 RA 风险的常见变异。Arg620Trp 几乎肯定是唯一的常见因果变异。
